Method of isomerizing a polyene aldehyde



Patented Apr. 27, 1954 UNITED STATES PATENT OFFICE 2,676,989 METHOD or ISOMERIZING A POLYENE' ALDEHYD John D. Cawley, Charles D. Robeson, and Wilbert J. Humphlett, Rochester, N. Y., assignors to Eastman Kodak Company, Rochester, N. Y., a corporation of New Jersey 7 No Drawing. Application September 11, 1951, Serial No. 246,161

19 Claims.

This invention relates to methods of makin a e-unsaturated l-cyclohexen-l-ylic polyene aldehydes and is particularly concerned with the preparation of vitamin A aldehyde.

Materials exhibiting high vitamin A biological activity are characterized by a specific basic structure, with the only diiierence being the nature of the terminal group. Thus the material may be an ester, acid, alcohol, aldehyde, ether or the like, but must have the basic structure H C CH3 3 CH3 CH3 with Z being --CH2OH; -COOH; -CHO;

--COOl'1,; --CH2OR; or the like, R being a hydrocarbon radical. Any change in the position of even a single double bond, or saturation of one of the double bonds, or change in the position of a substituent methyl group, or the addition of another substituent group either greatly reduces or entirely destroys the vitamin Abiological activity of the material.

For these reasons, the synthesis of vitamin A has been a difiicult problem, particularly in view of the fact that the materials of the vitamin A series are unstable and readily decomposed'or isomerized. Thus, most proposed syntheses of vitamin A have included either a Reformatsky or a Grignard reaction leading to a hydroxylic compound, usually an ester, as typified by the a,B-dihydro-fi-hydroxy vitamin A ester of the formula HaC CH3 or the diol of the formula or the hydroxy fi-ionylideneacetic acid ester of HsC CHa CH3 OH:

and the dehydration product of the diol comprises two possible isomers besides the desired vitamin A ester, namely,

HaC CH3 CH3 CH3 while the hydroxy p-ionylidene acetic acid ester dehydrates to give the isomer H3O CH3 The shifting of the unsaturation and interposition of a CI-I2- group in the chain gives compounds largely devoid of vitamin A biological activity and difiicult to convert to the desired compounds.

It is'accordinglyan object of this invention to provide an improved method of making afi-Llnsaturated, completely conjugated l-cyclohexenl-ylic polyene compounds.

aAnother object of the invention is to provide a new method 9; convertin undesired isomers of the compounds of the vitamin A series to the desired compounds.

Another object of the invention is to facilitate vitamin A syntheses which include a Grignard, Reformatsky or similar reaction yielding a hydroxy compound which ordinarily dehydrates in a useful method for obtaining a,B-unsaturated I l-cyclohexen-l-ylic polyene aldehydes from 2- cyclohexen-l-ylidem'c isomers thereof.

Another object of the invention is to provide a method of making vitamin A aldehyde having the vitamin A structure from material having the chemical composition of vitamin A aldehyde but a different structural configuration.

' Another object of the invention is to convert vitamin A-inactive material to vitamin A aldehyde.

' Another object of the invention is to increase the yield of vitamin A in syntheses involving dehydration of a hydroxyl compound by providing a new and improved method of altering the structural configuration resulting from such dehydration.

Other objects will be apparent from the description and claims which follow.

These and other objects of the invention are successfully attained by means of the present invention as described more fully hereinafter with reference to certain preferred embodiments thereof.

In accordance with this invention, an ocfi-llllsaturated, completely conjugated l-cyclohexen- 11-y1ic polyene is obtained by treating the prod- ,uct obtained by dehydrating and hydrolyzing a hydroxy polyene acetal and preferably a hydroxylic vitamin A dialkyl acetal, as described more fully hereinafter, and postulated as being a 2-cyclohexen-l-ylidenic aldehyde of the formula HaC CH3 wherein R is an unsaturated aliphatic hydrocarbon radical containing at least five carbon atoms and including a single chain -CH2 group, with .a basic catalyst, and thereby converting the 2- cyclohexen-i-ylidenic aldehyde to an a,,BllnSatllrated, completely conjugated l-cyclohexen-lylic polyene aldehyde containing no -CH2-- group in the aliphatic hydrocarbon radical.

We have discovered that, unlike the acids, esters and ethers of the vitamin A series, the aldehydes readily rearrange to the desired 0a,,8-l1I1- saturated completely conjugated structure when treated with a catalytic amount of material having a basic character and that such rearrangement takes place in nearly quantitative yield with no equilibrium mixture being formed.

Thus, by means of this invention, vitamin A syntheses can be effected through steps involving dehydration of hydroxyl compounds wherein isomerization of the unsaturated linkages normally occurs, provided the terminal group is an aldehyde group or readily convertible to an aldehyde group whereby the compounds are readily 4 rearranged to the desired structural configuration. The invention is applicable for preparation of /3ionylideneacetaldehyde and is particularly useful for preparing vitamin A aldehyde which is readily reduced to vitamin'A alcohol.

The 2 cyclohexen l ylidenic compounds treated in accordance with this invention and having the formula (R)CHO have from five to ten carbon atoms in the aliphatic hydrocarbon radical R. The aliphatic chain contains but a single --CH2 group, and this group is in an even-numbered position from the ring. In the case of the ten-membered radical, the radical includes a substituent methyl group on the carbon atoms in the three and seven positions from the ring. In the remaining shorter chain compounds, there is a substituent methyl group on the third carbon atom from the ring.

The process embodying this invention is preferably carried out with the 2-cyclohexen-1-ylidenic aldehyde dissolved in an organic solvent such as benzene, toluene, petroleum ether, ethyl ether or the like. The conversion to the desired l-cyclohexen-l-ylic aldehyde is desirably promoted by basic catalysis. Any of the well-known materials exhibiting a basic character can be employed including both organic and inorganic materails. Suitable materials include the inorganic hydroxides, salts of strong bases and weak acids, organic bases such as amines, and the like. The amount of basic material is not critical, trace portions being effective to catalyze the conversion embodying the invention.

Typical basic materials which are suitable for use as catalysts include sodium hydroxide, potassium hydroxide, potassium acetate, sodium acetate, pyridine, lutidine, picolines, aniline, morpholine, sodium aluminum silicate, sodium ethylate, aluminum alkoxides, ammonium hydroxide, piperidine, alkaline soaps and the like. "The 2-cyclohexen-1-ylidenic aldehydes which are treated in accordance with this invention can be prepared in any suitable manner. For example, the aldehyde, 9-(2,6,6-trimethyl-2- ,cyclohexen l-ylidene) -3,7-dimethyl-2,4,6-nonatrien'e-l-al can be prepared by condensing ,8- ionone with a propinyl halide to form a propinyl carbinol, condensation of this carbinol with a dialkyl acetal of p-ketobuty'raldehyde followed by hydrogenation of the acetylenic linkage to form a vitamin A diacetal-2,3,6,'7-tetrahydro-3,7-diol, and dehydration of this diol with phosphorous oxychloride and pyridine to a 2- cyclohexen-1- ylidenic enol ether corresponding to the desired 2-cyclohexen-l-ylidenic aldehyde. The enol ether is then hydrolyzed With mineral acid to the 2-cyclohexen-l-ylidenic aldehyde having the structural formula HzC CH:

The method of synthesizing Z-cyclohexen-lylidenic aldehydes in this manner is described in greater detail in the copending= application of HaC CH:

The aldehyde having the CH2- group in the 4 position from the ring can be prepared by substantially the same process as employed for the aldehyde having such group in the 8 position from the ring with the exception that the dehydration of the '7-hydroxy compound is effected prior 7 to partial hydrogenation of the acetylenic linkage. The aldehyde having the -CI-l2- group in the 6 position from the ring can be prepared by first condensing the propargyl halide with the dialkyl acetal of e-ketobutyraldehyde and dehydrating the resulting carbinol, condensing the afi-HI'lSat'llIfitGd dehydration product with ,e-ionone, hydrogenating the acetylenic linkage to an olefinic linkage, dehydrating the resulting I-hydroxy acetal to the corresponding enol ether and hydrolyzing the enol ether to the Z-cyclohexen-l-ylidenic aldehyde. The shorter chain 2-cyclohexen-l-ylidenic aldehydes can be prepared by like processes.

In accordance with this invention, the Z-cyclohexen-l-ylidenic aldehydes which are largely devoid of vitamin A activity are then rearranged by basic catalysis to vitamin A aldehyde which is readily reduced to vitamin A alcohol by wellknown reduction processes for converting aldehydes to alcohols. Various mechanisms may be advanced to explain the conversion of a hydroxylic vitamin A dialkyl acetal to vitamin A aldehyde by dehydration, with a basic catalyst as described herein, without changing the operative steps set out.

The invention is illustrated by the following examples of preferred embodiments. violet absorption data (E values) in the following examples were determined in ethanol in accordance with usual practice.

Example 1 A 0.58 g. portion of 9-(2,6,6-trimethyl-2-cyclohexene l-ylidene)-3,7-dimethyl-2,4=,6-nonatriene-l-al having mi"... (328 mp)=900 hydrolysis and treatment.

ing solution was added 67 was recovered, the rearrangement on passage through the alkaline adsorbent having been effected in a yield of 67%.

Example 2 A 1.0 g. portion of the aldehyde, 9-(2,6,6-trimethyl 2-cyclohexene-l-ylidene) -3,7-dimethyl- 2,4,6-nonatriene-l-al having Ei'f (328 m =794 was dissolved in 5 cc. of benzene. To a 1 ml. aliquot was added two drops of pyridine and the mixture was allowed to stand overnight at room temperature. The pyridine catalyzed rearrangement to vitamin A aldehyde having x maximum=370 m A similar sample treated with the non-basic pyridine hydrochloride remained unchanged at A maximum=328 m A sample treated with iodine solution, a common isomerization catalyst, similarly remained unchanged.

Example 3 Another aliquot, as in Example 2, was treated with a pinch of synthetic sodium aluminum sillcats and allowed to stand overnight at room temperature. It Was found that the aldehyde having A max.=328 m was converted to vitamin A aldehyde having k max.=3'70 m Examples! An 0.8 g. sample of 2-cyclohexen-1-y1idenic aldehyde having Eff (330 m =705 ethanol. To the result- 9 drops of 0.5 N. potassium hydroxide solution and the mixture was alwas dissolved in 6 cc. of

i lowed to stand at room temperature for three The ultrahours. The product was washed with water and dried over anhydrous sodium sulfate to give vitamin A aldehyde having Elie, (370 my.) :527

Example 5 product was vitamin A aldehyde having The rearrangement of other 2-cyclohexen-lylidenic aldehydes is catalyzed by other wellknown materials of basic character in similar fashion.

The invention thus provides a highly efiective method of obviating the troublesome isomerization of compounds of the vitamin A series during dehydration following a Grignard or Reformatsky reaction. The 2-cyclohexen-1-ylidenic aide-- hydes, unlike other 2-oyclohexen-1-ylidenic compounds such as esters or the like, readily rearrange in high yield to the desired completely conjugated, ii-unsaturated l-cyclohexen-l-ylic aldehydes when treated with a basic material in accordance with this invention.

Although the invention has been described in considerable detail with reference to certain preferred embodiments thereof, it will be understood that variations and modifications can be effected within the spirit and scope of the invention as described hereinabove and as defined in the appended claims.

We claim:

1. The method of making an a, 8-unsaturated, completely conjugated l-cyclohexen-l-ylic polyene aldehyde which comprises treating a solution, in an organic solvent, of a 2-cyclohexenl-ylidenic aldehyde of the formula (R)CHO -CHa (R)OHO wherein R is an unsaturated aliphatic hydrocarbon radical containing at least five and not more than ten carbon atoms and including a single chain CH2 group, said CH2 group being in an even-numbered position from the ring, with a basic catalyst, and thereby converting said Z-cyclohexen-l-ylidenic aldehyde to an nip-unsaturated completely conjugated l-cyclohexen-l-ylic aldehyde containing no -CI-I2 group in the aliphatic hydrocarbon radical.

3. The method of making an a,,8-unsaturated, completely conjugated l-cyclohexen-l-ylic polyene aldehyde which comprises treating a solution, in an organic solvent, of a 2-cyclohexenl-ylidenic aldehyde of the formula (ID-CHO wherein R is an unsaturated aliphatic hydrocarbon radical containing five carbon atoms including a substituent methyl group on the third carbon atom from the ring and including a single chain CH2 group, said CH2 group being in an even-numbered position from the ring, with a basic catalyst, and thereby converting said 2-cyclohexen-l-ylidenic aldehyde to an O B-unsaturated completely conjugated l-cyclohexenl-ylic aldehyde containing no -CH2-- group in the aliphatic hydrocarbon radical.

4. The method of making an 11,,8-11I1S2tfil1l2tl16d, completely conjugated l-cyclohexen-l-ylic polycne aldehyde which comprises treating a solution, in an organic solvent, of a z-cyclohexenl-ylidenic aldehyde of the formula (R) OHO wherein R is an unsaturated aliphatic hydrocarbon radical containing ten carbon atoms including a substituent methyl group on the third and the seventh carbon atoms from the ring and including a single chain CH2 group, said CH2 group being in an even-numbered position from the ring, with a basic catalyst, and thereby converting said 2-cyclohexen l-ylidenic aldehyde to an afi-unsaturated completely conjugated l-cyclohexen-l-ylic aldehyde contain ing no --CH2- group in the aliphatic hydrocarbon radical.

5. The method of making an a,/3-unsaturated, completely conjugated polyene aldehyde which comprises treating a solution, in an organic solvent, of a 2-cycloheXen-1-ylidenic aldehyde of the formula HaC CH3 CH3 (13H:

with a basic catalyst and thereby converting said 2-cycloheXen-1-ylidenic aldehyde to vitamin A aldehyde of the formula CH3 CH3 6. lhe method of making an il-unsaturated, completely conjugated polyene aldehyde which comprises treating a solution, in an organic solvent of a 2-cyclohexen-l-ylidenic aldehyde of the formula H3O CH3 JHQ (lira KWIOHCH=OCHQOH=CHC=CH one V-Cfla with a basic catalyst and thereby converting said 2-cycloheXen-1-ylidenic aldehyde to vitamin A aldehyde of the formula HaC CH3 '7. The method of making an l p-unsaturated, completely conjugated polyene aldehyde which comprises treating a solution, in an organic solvent, of a 2-cycloheXen-l-ylidenic aldehyde of the formula with a basic catalyst and thereby converting said 9 2-cyclohexen-l ylidenic aldehyde to vitamin A aldehyde of the formula H30 CH3 8. The method of making vitamin A aldehyde which Comprises treating a solution, in an organic solvent, of a Z-cyclohexen-l-ylidenic aldehyde of the formula with a basic catalyst and thereby converting said z-cyclohexen-l-ylidenic aldehyde to vitamin A aldehyde of the formula 9. The method of making vitamin A aldehyde which comprises treating an aldehyde of the formula (R)CHO wherein R is an unsaturated aliphatic hydrocarbon radical containing ten carbon atoms includin a substituent methyl group on the third and seventh carbon atoms from the ring and including a single chain CI-I2 group, said -CH2- group being in an even-numbered position from the ring, with an inorganic base and thereby converting said aldehyde to vitamin A aldehyde.

10. The method of making vitamin A aldehyde which comprises treating an aldehyde of the formula HaC CH:

said

lid.

wherein R is an unsaturated aliphatic hydro.- carbon radical containing 10 carbon atoms including a substituent methyl group on each of the carbon atoms in the third and seventh positions from the ring and including a single CHz-- group, said --CH2- group being in an evennumbered position from the ring, and thereby converting said aldehyde to vitamin A aldehyde.

12. The method of makingvitamin A aldehyde which com-prises filtering through a body of sodium aluminum silicate adsorbent a solution, in an organic solvent, of an aldehyde of the. formula I 1' HsC wherein R is an unsaturated aliphatic hydrocarbon radical containing 10 carbon atoms including a substituent methyl group on each of the carbon atoms in the third and seventh posi tions from the ring and including a single -CII2- group, said C'I-Iz group being in an evennumbered position from the ring, and thereby converting said aldehyde to vitamin A aldehyde.

13. The method of making vitamin A aldehyde which comprises treating an aldehyde of the formula CH3 CE:

with an inorganic base and thereby converting said aldehyde to vitamin A aldehyde.

14. The method of making vitamin A aldehyde which comprises treating an aldehyde of the formula with an organic base and thereby converting said aldehyde to vitamin A aldehyde.

15. The method of making vitamin A aldehyde which comprises treating with a basic catalyst the aldehydic product, isomeric to vitamin A -aldehyde, having A max.=328 m and being the product obtained by dehydration and hydrolysis of a hydroxylic vitamin A dialkyl acetal.

16. The method of making vitamin A aldehyde which comprises treating with a basic catalyst the aldehydic product, isomeric to vitamin A aldehyde, having A max.=328 m and being the product obtained by dehydration and hydrolysis of a vitamin A diol dialkyl acetal of the formula 17. The method of making vitamin A aldehyde 1 1 which com-prises treating, with an alkaline adsorbent, an aldehyde of the formula and thereby converting said aldehyde to vitamin A aldehyde.

18. The method which comprises dehydrating and hydrolyzing a hydroxylic' vitamin A dialkyl acetal and treating the product; thereby obtained with a basic catalyst.

19. The method which comprises dehydrating 12 and hydrolyzing a vitamin A diol dialkyl acetal of the formula and treating the product thereby obtained with a basic catalyst.

OTHER REFERENCES Karrer et a1., Helv. Chim. Acta., vol. 311, pp. 1055-1062 (1948).

Karrer, Carotenoids," Elsevier Pub. (30., New

York (1950), p. 183. 

1. THE METHOD OF MAKING AN A,B-UNSATURATED, COMPLETELY CONJUGATED 1-CYCLOHEXEN-1-YLIC POLYENE ALDEHYDE WHICH COMPRISES TREATING A SOLUTION, IN AN ORGANIC SOLVENT, OF A 2-CYCLOHEXEN1-YLIDENIC ALDEHYDE OF THE FORMULA 